The RET gene encodes a receptor tyrosine kinase that is expressed in neural crest-derived cell lineages. The RET receptor plays a crucial role in regulating cell proliferation, migration, differentiation, and survival through embryogenesis. Activating mutations in RET lead to the development of several inherited and noninherited diseases. Germline point mutations are found in the cancer syndromes multiple endocrine neoplasia (MEN) type 2, including MEN 2A and 2B, and familial medullary thyroid carcinoma. These syndromes are autosomal dominantly inherited. The identification of mutations associated with these syndromes has led to genetic testing to identify patients at risk for MEN 2 and familial medullary thyroid carcinoma and subsequent implementation of prophylactic thyroidectomy in mutation carriers. In addition, more than 10 somatic rearrangements of RET have been identified from papillary thyroid carcinomas. These mutations, as those found in MEN 2, induce oncogenic activation of the RET tyrosine kinase domain via different mechanisms, making RET an excellent candidate for the design of molecular targeted therapy. Recently, various kinds of therapeutic approaches, such as tyrosine kinase inhibition, gene therapy with dominant negative RET mutants, monoclonal antibodies against oncogene products, and nuclease-resistant aptamers that recognize and inhibit RET have been developed. The use of these strategies in preclinical models has provided evidence that RET is indeed a potential target for selective cancer therapy. However, a clinically useful therapeutic option for treating patients with RET-associated cancer is still not available.

https://www.umcg.nl/SiteCollectionDocuments/Zorg/ZOB/S/Schildklierkanker/RET%20as%20a%20diagnostic%20and%20terapeutic%20target.pdf

RET as a diagnostic and therapeutic target in sporadic and hereditary endocrine tumors

/pdf/health-effects-of-the-chernobyl-accident-and-special-health-4t3u0josfb.pdf

Health Effects of the Chernobyl Accident and Special Health Care Programmes

26 April 2006 marks the 20th anniversary of the Chernobyl accident. On this occasion, the World Health Organization (WHO), within the UN Chernobyl Forum initiative, convened an Expert Group to evaluate the health impacts of Chernobyl. This paper summarises the findings relating to cancer. A dramatic increase in the incidence of thyroid cancer has been observed among those exposed to radioactive iodines in childhood and adolescence in the most contaminated territories. Iodine deficiency may have increased the risk of developing thyroid cancer following exposure to radioactive iodines, while prolonged stable iodine supplementation in the years after exposure may reduce this risk. Although increases in rates of other cancers have been reported, much of these increases appear to be due to other factors, including improvements in registration, reporting and diagnosis. Studies are few, however, and have methodological limitations. Further, because most radiation-related solid cancers continue to occur decades after exposure and because only 20 years have passed since the accident, it is too early to evaluate the full radiological impact of the accident. Apart from the large increase in thyroid cancer incidence in young people, there are at present no clearly demonstrated radiation-related increases in cancer risk. This should not, however, be interpreted to mean that no increase has in fact occurred: based on the experience of other populations exposed to ionising radiation, a small increase in the relative risk of cancer is expected, even at the low to moderate doses received. Although it is expected that epidemiological studies will have difficulty identifying such a risk, it may nevertheless translate into a substantial number of radiation-related cancer cases in the future, given the very large number of individuals exposed.

https://iopscience.iop.org/article/10.1088/0952-4746/26/2/001/pdf

Cancer consequences of the Chernobyl accident: 20 years on

Summary The Chernobyl nuclear accident on 26 th April, 1986, led to a massive release of radionuclides into the environment. Although vast areas of Europe were affected by Chernobyl-related ionising radiation, the accident had the greatest impact in Belarus, Ukraine, and the Russian Federation. Epidemiological studies that have investigated the link between the Chernobyl accident and cancer have largely focused on malignant diseases in children, specifically thyroid cancer and leukaemia. There is good evidence to suggest that rates of thyroid cancer in children from the countries that were formally part of the Soviet Union have risen as a consequence of the Chernobyl accident. The findings for childhood leukaemia are less conclusive. Overall rates for this disease do not seem to have been affected by the Chernobyl-related ionising radiation, but there may be a larger risk of infant leukaemia in contaminated areas of Europe. Among adult populations, there is no strong evidence to suggest that risk of thyroid cancer, leukaemia, or other malignant disease has increased as a result of the Chernobyl accident.

https://www.thelancet.com/pdfs/journals/lanonc/PIIS1470204502007271.pdf

Chernobyl-related ionising radiation exposure and cancer risk: an epidemiological review

Ron, E. Ionizing Radiation and Cancer Risk: Evidence from Epidemiology. Radiat. Res. 150 (Suppl.), S30-S41 (1998). Epidemiological studies provide the primary data on the carcinogenic effects of radiation in humans. Much of what is known has come from studies of the atomic bomb survivors, and to a lesser extent from patients receiving radiotherapy. These studies demonstrate that exposure to moderate to high doses of radiation increases the risk of cancer in most organs. For all solid cancers combined, cancers of the thyroid, breast and lung, and leukemia, risk estimates are fairly precise, and associations have been found at relatively low doses (<0.2 Gy). Associations between radiation and cancers of the salivary glands, stomach, colon, bladder, ovary, central nervous system and skin have also been reported, but the relationships are not as well quantified. Associations between radiation and cancers of the liver and esophagus, and to a lesser extent multiple myeloma and nonHodgkin's lymphoma, have been reported in a few studies, but results are inconsistent. Chronic lymphocytic leukemia, Hodgkin's disease, and cancers of the pancreas, prostate, testis and cervix have rarely been linked to radiation exposure. A linear no-threshold model adequately describes the dose-response relationship for solid cancers, although at extremely high doses the risk appears to flatten out. Because few populations have been followed until the end of life, the temporal patterns of risk are not completely known. An increased risk, however, does continue for several decades. In contrast, radiation-related leukemias begin to occur shortly (2-3 years) after exposure and, at least in the A-bomb survivors, a linear-quadratic dose response seems to fit the data better than a pure linear model. Radiation does not act entirely in isolation. It can interact with other carcinogens, e.g. tobacco or chemotherapeutic agents, and with host factors such as age at exposure, gender or reproductive history. Interactions with medical interventions or with certain heritable mutations have also been suggested. While the studies of high-dose exposures are essential for understanding the overall biological consequences of radiation exposure, the public is more concerned about the long-term health effects from protracted exposures at low doses. Unfortunately, the inherent limitations of epidemiology make it extremely difficult to directly quantify health risks from these exposures. While most epidemiological data are compatible with linear extrapolations from exposures at high doses or high dose rates, they cannot entirely exclude other possibilities. As the field of epidemiology advances, understanding more about the health effects of prolonged and low-dose exposures will be the next

Ionizing radiation and cancer risk: evidence from epidemiology

The thyroid cancer incidence in the Ukraine among those born in the period 1968–1986 was analyzed with the aim to identify the enhancement due to the Chernobyl accident. Since any Ukrainian data referring to the time period before the accident are scarce and the variation of spontaneous incidences in other countries is immense, the Ukrainian incidences in the period 1986–1989 were used to estimate the baseline risk. Following 1990, the incidence in the southern part of the Ukraine increased by about 30%, independent of age. In the other parts the increase of the incidence depended on age at exposure. In the age group of 9-year-old children, the incidences in three regions defined as the `high-dose area', the northern, and the middle oblasts, increased by factors of 50, 20, and 6, respectively. These rates (1991–1995) are well above spontaneous rates in other countries. In the age group of 17-year-old juveniles, the incidence increased by a factor of 6 for the `high dose area' and in the three northern oblasts, whereas in the nine `middle' oblasts it was similar to the incidence of the `southern' Ukraine. These rates are within the range found in other countries.

Thyroid cancer incidence in the Ukraine after the Chernobyl accident: comparison with spontaneous incidences.

In the Zhytomyr region, about 52 000 measurements of the 131I activity in thyroids were performed. On the basis of these measurements, individual doses have been assessed for the people monitored and age-dependent average doses have been estimated for those settlements with more than 11 direct measurements. In order to estimate the pattern of thyroid exposure in the Zhytomyr region, these doses have been interpolated or extrapolated to population groups who were not monitored during May–June 1986. For this purpose, a model has been developed based on a correlation between thyroid dose estimates with the 137Cs deposition and the co-ordinates of the settlements relative to Chernobyl. Collective doses of people who were born in the years 1968 to 1986 were calculated. The radiation-induced thyroid cancer incidence in the period 1991 to 1995 was assessed by subtracting the spontaneous incidence from the observed incidence. The result is considerably lower than that observed in longer periods after external exposures. Possible reasons for this difference are discussed.

Thyroid dose and thyroid cancer incidence after the Chernobyl accident: assessments for the Zhytomyr region (Ukraine)

The thyroid doses of 49 360 inhabitants of Pripjat evacuated after the accident at Chernobyl were reconstructed During their evacuation most of the evacuees passed through highly contaminated territories The evaluation of a large-scale public survey showed that only about 50% of the evacuees had left the contaminated areas within 5 days and that 30% of them stayed there for more than 30 days As a first step, the model of dose estimations was improved, and thyroid doses were assessed for the group of evacuees for whom the131I activity in the thyroids was measured The131I incorporation during the first 5 days after the accident was described by a single-intake model (inhalation); later incorporations were assumed to be proportional to the radioiodine activity in milk As a second step, the correlation between the calculated doses andindividual parameters (place of residence in Pripjat, intake of stable iodine, and age at the time of the accident) was described by an empirical equation This equation was applied to all evacuees who completed the questionnaires of the public survey Previous dose assessments were found to overestimate the thyroid doses especially for the younger evacuees On the basis of these estimations, collective doses and the resulting radiation risks for thyroid cancer were assessed for different age groups

G. M. Goulko

Papers

Thyroid cancer incidence in the Ukraine after the Chernobyl accident: comparison with spontaneous incidences.

Thyroid dose and thyroid cancer incidence after the Chernobyl accident: assessments for the Zhytomyr region (Ukraine)

Estimation of 131I thyroid doses for the evacuees from Pripjat